Uterine leiomyoma Uterine fibroids are a highly prevalent disease, but the fundamental causes of leiomyoma growth and development remain poorly understood. Our past studies have suggested that the altered extra cellular matrix (ECM) in fibroids might affect fibroid growth and development. In the past year, we found dysregulated expression of ATF-3 was a possible link between mechanical stress and fibroid development. In another study, we found that elevated levels of TGF-beta in fibroids led to increased expression of the ECM protein versican. Also during the past year, in a collaborative effort with the Drs. Wood and Venkatesan, the unit began a trial of MRI-guided high frequency ultrasound (HIFU) treatment for fibroids. In addition, we completed analysis of a case series examining the possible impairment of ovarian function by myomectomy (removal of fibroids). In the coming year, we plan to dissect the altered mechanical signaling in fibroids in greater detail and we also plan to expand studies of HIFU as a treatment modality for uterine fibroids. Endometriosis and Chronic Pelvic Pain In the past year in collaboration with Dr. Nieman, Dr. Stratton concluded a study of raloxifene for treatment of endometriosis-related pelvic pain. Contrary to expectations, raloxifene appeared to hasten, not prevent, the recurrence of pelvic pain. In collaboration with Drs. Greene and Sinaii, the group led by Dr. Stratton also examined the relationship between disease severity and patient characteristics from 1000 women with endometriosis. Using this approach the group devised a model of the characteristics of endometriosis lesions that were associated with pain. In the coming year, the group will conclude a clinical study of the hypothalamic pituitary-adrenal-axis in women with chronic pelvic pain and endometriosis. Assessment and preservation of ovarian function in women and girls undergoing cancer treatment Many young girls and women are cancer survivors but find that their reproductive function is irreparably damaged by chemotherapy or radiation. In the past year, the unit tested a murine model of medical treatment prior to chemotherapy. The model confirmed efficacy of pre-treatment with GnRH-therapy, which appeared to act by reducing apoptosis in ovaries of pre-treated mice. In the coming year we plan to investigate the mechanism by which GnRH-antagonist functions in the murine model and launch a clinical study of GnRH-agonist treatment prior to chemotherapy in young women. Infertility and reproductive health disparities Our unit has continued to conduct studies of infertility and reproductive health disparities. In the past year Dr. Armstrong was an investigator in a study that examined reproductive health disparities in 130,000 assisted reproduction cycles (ART). The study supported our prior work and revealed that the likelihood of live birth was reduced in women of African-American and Asian women. The reasons for this disparity remain unclear. To encourage research on reproductive health disparities, Dr. Armstrong chaired a meeting at NIH on Reproductive Problems in Women of Color in July 2009. The meeting spawned new studies and collaborations. During the past year, we also continued clinical studies of infertility related to evidence-based and cost-effective infertility care. We modeled the effect of age and FSH levels on cost of a live-born child at assisted reproduction. In another study we examined the difference between age-related increases in FSH and increases in FSH prior to age 35. In the coming year, we plan to examine the pathophysiology underlying ovarian hyperstimulation syndrome (OHSS), a major risk factor for women pursuing assisted reproductive technologies. Role of BRX (also known as AKAP13) in cardiac development We have continued our study of the protooncogene, BRX, cloned by our group (also known as AKAP13) and the study of the murine model of targeted deletion of the BRX gene. In collaboration with Dr. Kino, studies in the past year focused on the reduced size of the spleen in haplo-insufficient mice. Investigation of the phenotype led to the discovery that BRX was involved in the response of lymphocytes to osmotic stress. In fact, BRX was found to be an essential factor for activation of the nuclear factor of activated t-cells 5 (NFAT5) via a p38MAPK-dependent cascade with JIP4. This observation indicates that one role of BRX is to function as link to integrate osmotic stress and inflammation. In the coming year, we plan to further characterize the role of BRX in development and cancer using our murine model.